| Structural highlights
Function
[BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2]
Publication Abstract from PubMed
Starting from lead compound 4, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF3 group delivered an excellent pharmacological profile with a pKa of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin- 3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Abeta levels in mice, rats, and dogs in acute and chronic treatment regimens.
Synthesis of the Potent, Selective, and Efficacious beta-Secretase (BACE1) Inhibitor NB-360.,Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Holzer P, Hurth K, Voegtle M, Frederiksen M, Rondeau JM, Tintelnot-Blomley M, Jacobson LH, Staufenbiel M, Laue G, Neumann U J Med Chem. 2021 Apr 22;64(8):4677-4696. doi: 10.1021/acs.jmedchem.0c02143. Epub , 2021 Apr 12. PMID:33844524[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
- ↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
- ↑ Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Holzer P, Hurth K, Voegtle M, Frederiksen M, Rondeau JM, Tintelnot-Blomley M, Jacobson LH, Staufenbiel M, Laue G, Neumann U. Synthesis of the Potent, Selective, and Efficacious beta-Secretase (BACE1) Inhibitor NB-360. J Med Chem. 2021 Apr 22;64(8):4677-4696. doi: 10.1021/acs.jmedchem.0c02143. Epub , 2021 Apr 12. PMID:33844524 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c02143
|
